1. Field of the Invention
The present invention relates to novel antitumor polymeric compositions and methods of treatment therewith. More particularly, the invention relates to a pharmaceutical composition comprising an anthracene antitumor compound, particularly mitoxantrone, covalently conjugated to, or admixed with, a divinyl ether-maleic anhydride (MVE) copolymer.
2. Description of the Related Art
Macromolecules have been used as drug carriers in an attempt to prolong plasma levels of drugs presumably as a result of slow release of drugs from macromolecules and to achieve favorable uptake by the tumor cells. Among macromolecular carriers, divinyl ether-maleic anhydride (MVE) has been investigated extensively. MVE copolymer contains multiple anhydride rings, which allows easy functionalization with antitumor agents carrying nucleophilic groups such as --NH.sub.2, --OH and --SH. Furthermore, a carboxyl group is generated from each anhydride ring functionalized with a drug molecule. Therefore, MVE copolymer is capable of covalently binding a large number of lipophilic antitumor agents, while maintaining water solubility.
MVE copolymer has been covalently linked with various therapeutically active antitumor agents including 5-fluorouridine, daunomycin, adriamycin, .beta.-D-arabinofuranosylcytosine and methotrexate with varying results. Some of the MVE-linked agents demonstrated higher therapeutic efficacies and lower toxicities during in vivo antitumor evaluations while others showed no increase or were unstable under physiological conditions. MVE linked with methotrexate through the 2- or 4-amino groups of the pteridine ring of methotrexate showed only a slight increase in life span (% ILS) against L1210 leukemia in mice when compared with free methotrexate. MVE copolymer had a potentiating effect on the antitumor activity of 5-aza-2'-deoxy-cytidine but had no therapeutic benefit when used with cyclophosphamide under the same experimental conditions of tumor burden and treatment schedule. D. S. Zaharko et al., Canc. Treat. Rpts. 68(10): 1255-1264 (1984). U.S. Pat. No. 4,520,162 discloses MVE-copolymer conjugates of adriamycin, daunomycin and AraC.
The anthracene antitumor agents are a group of compounds having an anthracene moiety of which mitoxantrone and bisantrene are representative members. Mitoxantrone is indicated for treatment of acute nonlymphocytic leukemia in humans. While these agents exhibit excellent anti-tumor activity, they also exhibit strong toxicity to normal cells. For example, administration of mitoxantrone is associated with myelosuppression and cardiac abnormalities as well as other side effects. Therefore, any potentiation of the drug's antitumor effect would theoretically allow smaller doses of the drug to be administered over longer periods of time thereby avoiding or minimizing some of the undesirable adverse effects. It is therefore an object of the present invention to provide a method of potentiating the antitumor activity of such anthracene antitumor agents.